BRCA1 Alterations Research Articles

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer

The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Detection of BRCA1, and BRCA2 Alterations in Matched Tumor Tissue and Circulating Cell-Free DNA in Patients with Prostate Cancer in a Real-World Setting.

Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious BRCA1 and/or 2 mutations. Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of BRCA mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting. Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect. The presence or absence of mutations in the BRCA gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0-232) months. BRCA mutation was present in the patient's original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% [95% CI, 95.3-99.1%]. The adjusted concordance between metastatic samples and cfDNA was 93.5% [95% CI, 86.4-97.3%]. Of the patients who had a BRCA mutation detected in their prostate tissue, there was a 70% probability of detecting a BRCA mutation in the patient's cfDNA as well. For patients who did not have a detectable BRCA mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%. There is a high level of concordance between tissue and blood for BRCA mutations. Testing cfDNA can provide reliable information on BRCA mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new BRCA mutation later in the disease course is a rare event.

Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz–Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.

72P Treatments response in non-small cell lung cancer patients according to BRCA status on liquid biopsy: A retrospective analysis

NSCLC has to date a poor prognosis with life expectancy at five year of 26%. The development of precision medicine is going to improve the prognosis, but most of alterations are still lacking of clinical significance. Somatic BRCA alterations, is reported to be quite frequent in NSCLC, with a prevalence of 5.3-6.6%. However, no specific study to date specifically evaluated its prognostic and predictive role in this population of patients.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian carcinoma

ObjectiveARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. MethodsPatients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes. ResultsRucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C, and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit. ConclusionsExceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma.

Highlights from Recent Cancer Literature

Breaking Insights| September 16 2022 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Res (2022) 82 (18): 3189–3190. https://doi.org/10.1158/0008-5472.CAN-82-18-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record September 16 2022 Citation Highlights from Recent Cancer Literature. Cancer Res 15 September 2022; 82 (18): 3189–3190. https://doi.org/10.1158/0008-5472.CAN-82-18-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Although BRCA1/2 alterations have been reported to predict platinum sensitivity, BRCA1 alterations have not consistently correlated with platinum sensitivity in clinical trials. Menghi and colleagues have now identified an explanation for these discordant results. They found that in contrast to BRCA1/2 mutations, BRCA1 promoter methylation (BRCA1meth) was not correlated with response to platinum agents in triple-negative breast and ovarian cancer patients. In vivo studies revealed that BRCA1meth is lost during chemotherapy treatment, leading to BRCA1 reactivation and acquired platinum resistance. Expert Commentary: This study suggests that the reversibility of BRCA1meth may explain the inconsistent platinum efficacy observed in BRCA1-deficient tumors. Menghi F, Banda K, Kumar P, Straub R, Dobrolecki L, Rodriguez IV, et al. Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas. Science Translational Medicine 2022;14:eabn1926. doi: 10.1126/scitranslmed.abn1926. Promoter methylation of the... You do not currently have access to this content.

Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA.

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation.

1368P TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage response alterations (DDRm) – Exploration of tumor genetics associated with prolonged benefit

TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (11-gene panel). Enrolled men had received 1–2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. Confirmed objective response rate (primary endpoint; per RECIST 1.1; blinded independent central review [BICR]) was 29.8%. The molecular bases of prolonged clinical benefit with poly(ADP-ribose) polymerase inhibitors are incompletely understood, although limited evidence suggests that patients exhibiting large deletions in BRCA genes may experience extended benefit. Exploratory post hoc biomarker analyses assessed tumor genetics associated with prolonged antitumor benefit in TALAPRO-1. Tumor alterations were assessed using FoundationOne®CDx. Zygosity of tumor alterations was predicted using somatic-germline-zygosity. Prolonged benefit was assessed as radiographic progression-free survival ([rPFS]; RECIST 1.1/PCWG3; BICR) time to event or censoring. Data cutoff was Sept 4, 2020 (primary completion date). Of 104 men in the efficacy population, 16 had rPFS of ≥12 months. Of their 16 tumors, 15 (94%) had BRCA2 alterations, including 10 large structural variants (9 copy number loss, 1 rearrangement) and 5 short variants (SV; 4 homozygous). In contrast, only 6/27 (22%) men with rPFS <2.0 months exhibited BRCA2 alterations (1 rearrangement, 1 non-defined, and 4 SV with 2 homozygous). Of 61 men with rPFS <12 months but ≥2 months, 36 (59%) had BRCA2 alterations (9 copy number loss, 1 rearrangement, 21 SV [11 homozygous], 2 multiple alterations [1 homozygous], and 3 not defined). Conversely, TP53 alterations were less common for men with rPFS ≥12 months vs <2 months (2/16 vs 14/27; P=0.02 Fisher’s exact test, 2-tails), potentially reflecting negative prognosis or a subgroup less sensitive to PARP inhibition. Based on these retrospective, exploratory analyses of TALAPRO-1, men exhibiting prolonged benefit typically exhibited BRCA2 copy number loss or homozygous alterations, and lacked TP53 alterations.

Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound.

Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study. Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx. 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor. We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.

Análisis de polimorfismos en los genes BRCA1 y BRCA2 en una muestra poblacional de caninos de Uruguay

In non-ovariectomized female dogs, breast tumors are the most frequent neoplasms. There are several points where canine and human breast tumors have clinical and molecular similarities. BRCA1 and BRCA2 genes have been extensively studied in both species. Regarding dogs, alterations in BRCA1 and BRCA2 have been identified in the development of breast tumors in different breeds. In this work, it was proposed to study exons 22 and 23 of the BRCA1 gene and exons 11 and 27 of the BRCA2 gene, in female dogs. It was studied two groups of female dogs, with or without mammary tumors. Regarding the genetic study of 15 loci, six were polymorphic, all of them were singles nucleotides polymorphisms (SNPs), while the other nine were monomorphic. It was obtained a low allelic variability, but at the population level, the tumor group has greater variability than the control group. On the other hand, the different analyses of possible groupings were negative, and it was not possible to clearly define groups with the parameters it was used. The foregoing may be a consequence of numerous factors such as characteristics inherent to the populations studied, such as the size of both populations; the breeds studied; tumor diversity. As it was mentioned before, the genes studied in this work have been widely related to breast cancer, both in humans and in dogs. In the former, they have been highly implicated in hereditary tumors. In dogs, it do not have that information. In the present case, it was founded no relationship between each of the markers studied and the occurrence of mammary tumor between the problem group and the control group.

BRCA2 Alterations in Neuroendocrine/Small-Cell Carcinoma Prostate Cancer: A Case Series.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00091 JCO Precision Oncology no. 6 (2022) e2200091. Published online July 14, 2022. PMID: 35834759 BRCA2 Alterations in Neuroendocrine/Small-Cell Carcinoma Prostate Cancer: A Case Series Lynn Symonds , MD1xLynn SymondsSearch for articles by this author; Erik Konnick , MD2xErik KonnickSearch for articles by this author; Funda Vakar-Lopez, MD2xFunda Vakar-LopezSearch for articles by this author; Heather H. Cheng , MD, PhD1,3xHeather H. ChengSearch for articles by this author; Michael T. Schweizer , MD1,3xMichael T. SchweizerSearch for articles by this author; Peter S. Nelson , MD1,2,3,4xPeter S. NelsonSearch for articles by this author; Colin C. Pritchard , MD, PhD2,5xColin C. PritchardSearch for articles by this author; and Bruce Montgomery , MD1,6xBruce MontgomerySearch for articles by this author Show More 1Division of Medical Oncology, University of Washington, Seattle, WA2Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA4Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA5Brotman Baty Institute for Precision Medicine, Seattle, WA6VA Puget Sound and Precision Oncology Program for Cancer of the Prostate, Seattle, WA https://doi.org/10.1200/PO.22.00091 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologySUPPORTSupported by the Pacific Northwest Prostate Cancer SPORE CA097186 (P.S.N., B.M.); Prostate Cancer Foundation Challenge Awards (B.M., P.S.N.); CDMRP Awards W81XWH-18-1-0355 (P.S.N., C.C.P., B.M.), W81XWH-21-1-0264 (P.S.N.), W81XWH-17-2-0043 (H.H.C.), R01 CA234715 (P.S.N.), T32 CA009515 (L.S.).AUTHOR CONTRIBUTIONSConception and design: Peter S. Nelson, Bruce MontgomeryFinancial support: Peter S. NelsonAdministrative support: Bruce MontgomeryProvision of study materials or patients: Funda Vakar-Lopez, Heather H. Cheng, Peter S. Nelson, Colin C. PritchardCollection and assembly of data: Erik Konnick, Funda Vakar-Lopez, Heather H. Cheng, Colin C. Pritchard, Bruce MontgomeryData analysis and interpretation: Lynn Symonds, Erik Konnick, Heather H. Cheng, Michael T. Schweizer, Peter S. Nelson, Colin C. Pritchard, Bruce MontgomeryManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Erik KonnickConsulting or Advisory Role: RocheFunda Vakar-LopezConsulting or Advisory Role: AstraZenecaHeather H. ChengConsulting or Advisory Role: AstraZeneca, AstraZeneca (I)Research Funding: Sanofi (Inst), Janssen (Inst), Clovis Oncology (Inst), Color Genomics Foundation (Inst), Medivation/Astellas (Inst), Phosplatin Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: UpToDateOther Relationship: JanssenMichael T. SchweizerConsulting or Advisory Role: Resverlogix, AstraZeneca, PharmaIn, SanofiResearch Funding: Janssen (Inst), AstraZeneca (Inst), Roche (Inst), Pfizer (Inst), Zenith Epigenetics (Inst), Madison Vaccines, Inc (Inst), Immunomedics (Inst), Bristol Myers Squibb (Inst), Merck (Inst), Tmunity Therapeutics, Inc (Inst), SignalOne Bio (Inst)Peter S. NelsonConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Roche/Genentech, Bristol Myers SquibbResearch Funding: Genomic Health (Inst)Expert Testimony: VenableTravel, Accommodations, Expenses: Janssen OncologyColin C. PritchardConsulting or Advisory Role: AstraZeneca, Sana BiotechnologyResearch Funding: Color Genomics (I)Bruce MontgomeryResearch Funding: AstraZeneca (Inst), Janssen Oncology (Inst), Clovis Oncology (Inst), Astellas Pharma (Inst), Beigene (Inst)No other potential conflicts of interest were reported.

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects.

Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.

Abstract 4133: High prevalence and heterogeneity of emergence of BRCA reversion mutations at progression on niraparib treatment in BRCA-mutant metastatic castration-resistant prostate cancer (mCRPC) patients

Abstract In the phase 2 GALAHAD study (NCT02854436), the PARP inhibitor (PARPi) niraparib, was evaluated in heavily pre-treated patients with mCRPC and DNA-repair gene defects (DRD) who progressed after androgen-receptor (AR) targeted therapy and taxane-based chemotherapy. The results showed that objective response rate (ORR) was 34.2% for patients with measurable disease having biallelic BRCA1/2 alterations (n=76). The development of BRCA reversion mutations, a type of secondary mutation that restores protein function, has been proposed as a key resistance mechanism to PARP inhibition. We aimed to evaluate the relationship between reversion mutations and treatment response in BRCA1/2 altered patients treated with niraparib in the GALAHAD study. Thirty-three patients with biallelic BRCA alterations (excluding patients with homozygous deletions) had donated an end-of-treatment (EOT) ctDNA sample. We performed sequencing to detect reversion mutations using the Resolution Bioscience ctDx-HRD assay. Mutation patterns at baseline included splice site, nonsense, missense, and frameshift mutations, with the latter being the most common (24/33; 73%). No reversions were detected at baseline and the baseline BRCA alterations were detected at EOT for every patient. Most BRCA patients (28/33; 85%) had at least 1 reversion mutation (range: 1-38 different BRCA alterations) at EOT. Of the 28 patients with reversions, 5 were classified as low reversions: 3 patients had only one reversion mutation, 1 patient had 2 reversions at low allele frequency and 1 patient had 4 reversions at low allele frequency. Patients with reversion mutations showed better composite response (defined as ORR by RECIST 1.1, or CTC conversion to &amp;lt;5/7.5 mL blood, or ≥50% decline in prostate specific antigen) (74.2% vs 25.8%, p=0.01) and longer duration on treatment (median 6.9 vs 3.7 mo, p&amp;lt;0.05) compared to those without or low reversions. Additionally, patients with reversions trended to have longer median radiographic progression-free survival compared to those without or low reversions (8.1 vs 5.5 mo, p=0.12). In conclusion, the high prevalence of patients with BRCA reversion mutations and the displayed longer benefit from niraparib underscores the dependence of these tumors on BRCA mutation as an oncogenic driver and reversion mutations as a marker of secondary resistance to niraparib treatment. Citation Format: Karen Urtishak, Gerhardt Attard, Tokuwa Kanno, Shibu Thomas, Gary E. Mason, Byron Espina, Eugene Zhu, Natalie Hutnick, Mary Guckert, Adam del Corral, Mark Li, Angela Lopez-Gitlitz, Kim Chi, William Kevin Kelly, Evan Y. Yu, Karim Fizazi, Matthew Smith. High prevalence and heterogeneity of emergence of BRCA reversion mutations at progression on niraparib treatment in BRCA-mutant metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4133.

Comparative analysis of the targetable landscape in KRAS-mutant and wild-type pancreatic adenocarcinoma.

4155 Background: Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer deaths, with increased incidence among patients (pts) younger than 50 years old (yo). Small cohort studies suggest early-onset PC (EOPC, diagnosis at &lt; 50 yo) tumors may have a unique biology, harboring a higher proportion of KRAS wild-type status ( KRASWT) and enrichment of targetable mutations/fusions compared to non-EOPC. In addition, therapy targeting oncogenic fusions in KRASWT tumors has shown meaningful responses in PC pts. Here, we investigate the prevalence of fusions, mutations, and homologous recombination deficiency (HRD) in KRASWT PC to identify potential targets for therapeutic intervention, and compare EOPC to non-EOPC to better characterize EOPC differences. Methods: De-identified records from 4,956 PC pts with tumor biopsies sequenced using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq) were retrospectively reviewed. Fusions were detected from RNA-seq data via the Tempus bioinformatics pipeline. Mutations identified included germline and/or somatic single-nucleotide variants and insertions/deletions. HRD status was determined from RNA-seq data by the Tempus HRD test. Significance was determined as FDR-corrected p-values &lt; 0.05. Results: Across the entire cohort, 21% tumors were KRASWT. HRD was more frequent in KRASWT (7.9%) compared to KRASMUT (3.1%) tumors ( P&lt; 0.001). Significant somatic mutational differences between the KRASWT and KRASMUT cohorts included BRAF (5.0% vs 0.2%) , CDKN2A (5.4% vs 25%), ARID1A (3.6% vs 8.6%), CTNNB1 (1.3% vs 0.3%), and TSC2 (1.2% vs 0.1%) (all P&lt; 0.001). Actionable rearrangements were enriched in the KRASWTcohort (10% vs 2.1%, P&lt; 0.001); the most common fusion partners include NRG1, MET, RAF1, BRAF, NTRK1-3, FGFR 1-4, and RET. TMB-high (10 muts/Mb) and MSI-high were more common in KRASWT (2.9% and 1.0%) compared to KRASMUT (1.7% and 0.4%) tumors ( P= 0.015). Additionally, 382 pts were classified as EOPC. KRASWT tumors comprised 30% of EOPCs, 22% of the 50-70 yo cohort, and 17% of the &gt; 70 yo cohort. Germline (pathogenic/likely pathogenic) alterations in BRCA1 and BRCA2 were more frequent in EOPCs (2.0% and 4.5%) compared to the 50-70 yo (0.4% and 1.7%) and &gt; 70 yo (0.4% and 0.8%) cohorts ( P= 0.015 and &lt; 0.001, for BRCA1 and BRCA2 respectively). There were no statistical differences in actionable genes detected in EOPC vs non-EOPC. HRD was found at higher frequency in EOPC (5.4%) and decreased in age cohorts 50-70 yo (4.7%) and &gt; 70 yo (2.5%) ( P = 0.047). Rearrangements were more common in EOPC compared to non-EOPC (10% vs 1.1%, P&lt; 0.001). Conclusions: HRD, TMB-H/MSI-H and oncogenic rearrangements are more prevalent in KRASWT PC when compared with KRASMUT. These molecular analyses may provide additional therapeutic options for PC pts, warranting comprehensive genomic and transcriptomic profiling for this population.

Pathogenicity Reclassification of Genetic Variants Related to Early-Onset Breast Cancer among Women of Mongoloid Origin.

Background:Germline alterations in BRCA1, BRCA2, and other genes are responsible for early-onset breast cancer. However, up to 20% of molecular tests report genetic variant of unknown significance (VUS) or novel variants that have never been previously described and their clinical significance are unknown. This study aimed to reclassify variant of unknown significance (VUS) or novel variants by using the ActiveDriveDB database that annotates variants through the lens of sites of post-translational modifications (PTM). Methods:Our study included thirty-eighth young Buryat BC patients, belonging to the Mongoloid race and anthropologically to the Central Asia. Genomic DNA was extracted from the peripheral blood lymphocytes using the phenol/chloroform method. DNA library were prepared using the Hereditary Cancer SolutionTM kit (Sophia GENETICS, Switzerland) to cover 27 genes, such as ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. Paired-end sequencing (2 x 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results:We re-examined 135 rare variants (41 VUS, 25 conflicting, 64 benign and 5 new variants). We identified 10 out of 135 (7.4%) mutations that affected the sites of post-translational modification in proteins. Of 135 rare mutations, 1 benign variant was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM- mutations, 2 new and 1 benign variant were classified as proximal PTM- mutations and 1 benign and 1 conflicting variant were classified as direct PTM- mutations.Conclusions:For the first time, 7.4% (10 out of 135) of mutations that affected the sites of post-translational modification in proteins were identified among early-onset breast cancer women of Mongoloid origin.

BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects.

5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and &gt; 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]

The mutational profile of ER-, PR+, HER2- metastatic breast cancer.

1025 Background: ER-PR+Her2- breast cancer is a rare subtype occurring at approximately 1% of all breast carcinomas. Most of these cancers behave in an aggressive fashion with limited benefit from anti estrogen therapy, similar to triple negative breast cancer (TNBC). Better characterization of these tumors is needed for predicting clinical behavior, response to endocrine therapy, and eligibility for clinical trials. Here we sought to evaluate the mutational profile of a well curated set of ER-PR+HER2- metastatic breast cancers and compare to other receptor phenotypes. Methods: 2049 consecutive breast cancers submitted to Foundation Medicine for comprehensive genomic profiling (CGP) were included. ER, PR and HER2 expression were abstracted from submitted pathology reports. Cases without complete ER, PR and HER2 information in pathology reports were excluded. CGP was performed as previously described (Frampton, 2013). Results: Patient ages were similar across subgroups. Generally, ER-PR+HER2- tumors were rare (n = 23, 1.1%) and most similar to TNBC in their genomic profiles. These tumors harbored high rates of TP53 and BRCA1 alterations and low rates of PIK3CA, ESR1, and CDH1 alterations. Genomic loss of heterozygosity (gLOH) was similar in the ER-PR+HER2- and ER+PR+HER2-subtypes (8.18% and 8.66% respectively), and lower than TNBC (17.19%). Notably, a high rate of RB1 alterations were identified in the ER-PR+HER2- patients (13%, 3/23), numerically higher than the other subtypes. EGFR, MET, PTEN, CDKN2A and KRAS alterations were also observed at a higher frequency in ER-PR+Her2- cancers (8.7, 4.2, 39.1, 13.0 and 13.0% respectively) relative to the other subtypes. IO drug biomarkers including MSI, TMB and PD-L1 IHC were similar among the groups. Conclusions: The mutational profile for ER-PR+Her2- metastatic breast cancer more closely resembles TNBC than ER+ breast cancer. These data suggest molecular profiling may be a useful adjunct to optimize treatment strategies for this rare subset of cancers. Based on molecular characteristics, we recommend including ER-PR+Her2- patients in clinical trials for TNBC. Finally, genes including RB1, CKDN2A, PTEN, EGFR and MET are mutated at higher frequency in ER-PR+Her2- cancers than other subsets, suggesting unique biology with potential therapeutic implications. [Table: see text]

AI-enabled identification prediction of homologous recombination deficiency (HRD) from histopathology images.

3019 Background: Homologous recombination deficient (HRD) tumors are highly responsive to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitor (PARPi) therapy. Pathogenic BRCA-1 and BRCA-2 (BRCA1/2) alterations are key members of the HR DNA repair pathway but genomic instability status, including loss of heterozygosity, telomeric allelic imbalance and large scale state transitions across the genome are also predictive of HRD. HRD testing is currently performed by next generation sequencing which can take 2-4 weeks for results, has a high failure rate, requires significant tissue and is costly. We developed and tested the ability of an AI enabled platform to predict HRD status from the analysis of whole slide imaging of the diagnostic H&amp;E slide. This platform, iPREDICT-HRD is rapid, precise, and cost effective. Methods: The AI engine was trained on 120 H&amp;E slides that were used to identify tumor prior to manual microdisseection for HRD assessment by NGS. Histopathological features were extracted, followed by feature mapping to predict HRD status based on the results of NGS testing. ResNet AI algorithm was trained to segment, annotate and predict HRD status. 10 lac tiles of 256x256 size at 40x magnification were generated per pathological class. 70% of the data set was used for training and 30% for validation of the AI model. Results: Using single blinded clinical samples, iPREDICT-HRD tool detected HRD + ve samples with 99.3% accuracy with 100% sensitivity and 99% specificity in the test set. Patch-level predictions of HRD status demonstrated intra-tumor heterogeneity within the H&amp;E slides. Visual inspection of the heatmap suggested the presence of patches with high predictive ability of HRD status and this outperformed an average HRD score for slides with heterogeneity. Conclusions: AI-enabled prediction of HRD status can be accurately performed on diagnostic H&amp;E slides potentially yielding results quickly and afforadably, even when limited tissue is available for testing.